This invention relates to the manufacture of 4-amino-3-quinolinecarbonitriles, which can serve as intermediates for the synthesis of additional 4-amino-3-quinolinecarbonitrile analogues. Such substituted quinolines, as well as the pharmaceutically acceptable salts thereof, inhibit the action of certain protein kinases (PK) thereby inhibiting the abnormal growth of certain cell types.
The compounds derived from this invention are for example, useful in the treatment of polycystic kidney disease, colonic polyps, cancer, and stroke in mammals.
Throughout this patent application the quinoline ring system will be numbered as indicated in the formula below:

This invention also relates to the manufacture of 7-amino-thieno[3,2-b]pyridine-6-carbonitriles useful as intermediates in the synthesis of 7-amino-thieno[3,2-b]pyridine-6-carbonitrile analogues. Throughout this patent application the thieno[3,2-b]pyridine ring system will be numbered as indicated in the formula below:

Historically there are several methods for the preparation of 4-aminosubstituted quinolines and the two most frequent methods involve intramolecular Friedel-Crafts reactions or electrocyclic ring closures of N-(2-carboxyvinyl)-aniline derivatives at elevated temperatures. Cyclodehydration of suitable amide substrates via Vilsmeier type intermediates appears attractive but the literature is scarce and in the example below, the desired amino-quinoline species is unstable under the reaction conditions and the chloro-quinoline is favored [Meth-Cohn, O., Taylor, D. L. (1995) Tetrahedron, 51, 12869].
The approach described herein is favorable due to the relative ease of preparation of the cyanoacetamide portion from cyanoacetic acid and the desired aniline and suitably substituted aniline that results in the carbocyclic ring. One example exists in the literature where 3-chloroaniline is reacted via a variety of cyanoacetamides to form enaminonitriles, which undergo cyclization to 4-aminoquinolines in some cases. The conditions used to prepare the enaminonitrile are much harsher than those outlined herein and cyclization conditions in some examples do not result in cyclodehydration [Price, C. C., Boekelheide, V. (1946) J. Am. Chem. Soc., 68, 1246]. In addition, the compounds described in this invention contain significantly different substitution patterns.